S2 Table. Genetic syndromes displaying various craniofacial abnormalities, used to locate candidate genes for the study. Syndrome Symptoms Prevalence Genetic origin Aarskog syndrome Distinct facial features, such as: rounded face, Rare Mutations in FGDY1 (OMIM:100050) underdeveloped mid-portion of the face (maxilla), gene on X chromosome small nose with nostrils tipped forward [1] (anteverted), wide-set eyes, crease below the lower lip (hypertelorism) Alagille syndrome Distinct facial features, such as broad forehead, 1 in 70,000 Mutations in JAG1 gene (OMIM: 118450) pointed mandible and bulbous tip of the nose and [2] in the fingers Alfi's Syndrome Mental retardation, trigonocephaly, mongoloid 1 in 5 million Monosomy 9p or (OMIM: 158170) eyes, wide flat nasal bridge, anteverted nostrils, 9p22.2-3 deletion [3] long upper lip, cleft lip/palate, short neck, long digits mostly secondary to long middle phalanges Apert Syndrome Various manifestations of craniosynostosis with Between 1 in Mutations in FGFR2 (OMIM: 101200) cleft lip/palate. 65,000 to gene [4] 200,000 Beckwith- Characteristic facial appearance and indentations Rare Mutation or deletion of Wiedemann of the ears, a large tongue which may cause genes H19, KCNQ1OT1 Syndrome breathing, feeding or speech difficulties, one side or CDKN1C in 11p15.5 (OMIM: 130650) of the body grows more than the other chromosomal region [5- 7] Cohen Syndrome Abnormalities of the head, characteristic facial Rare Mutations in COH1 (OMIM: 216550) features including high-arched or wave-shaped gene [8] eyelids, a short philtrum, thick hair, and low hairline Cri-du-chat Abnormal larynx and epiglottis which causes a 1 in 50,000 Mutations in two Syndrome (OMIM: distinct sounding cry. The name literally means live births candidate genes: 123450). Other “cry of the cat.” Other symptoms include mental Semaphorine F name: 5p deletion retardation, small head (microcephaly). (SEMA5A) and delta syndrome Characteristic facial features at birth include a catenin (CTNND2), large nasal bridge, round face, wide-spaced eyes, potentially involved in low-set ears, and a down-turned mouth. As the cerebral development child gets older the facial features change and a [9] long, narrow face is more commonly observed Crouzon Syndrome Craniosynostosis disorder causing secondary 1 in 60,000 Mutations in FGFR2 (OMIM: 123500) alterations of the facial bones and facial structure. gene [10,11] Common features include hypertelorism, parrot- beaked nose, short upper lip, hypoplastic maxilla, and a relative mandibular prognathism Down Syndrome People with Down Syndrome have similar facial 1 in 600-1000 Extra copy of (OMIM: 190685). features including a flattened facial profile, live births. chromosome 21 in each Other name: upward slanting eyes, small over-folded ears, flat Trisomy 21 is cell. Each person with Trisomy 21 nose and small mouth with a protruding tongue. the most Down syndrome may They can also have low muscle tone, a shorter common have slightly different than typical neck, a single crease across the palm trisomy seen symptoms due to of the hand, heart defects, and varying levels of in live born variations in intellectual disability individuals chromosomal abnormalities (e.g. Partial or full copy of chromosome 21). Several candidate genes have been identified in Down syndrome critical region, such as DSCR1, DSCR2, DSCR3 and DSCR4 [12] and SHH [13] Edward Syndrome. Small head (microcephaly), small jaw/mouth 1 in 3000- Extra chromosome 18 in Other name: (micrognathia), low-set malformed ears, cleft 8000 live each cell. Trisomy 18 is Trisomy 18 lip/cleft palate, upturned nose, narrow eyelid births. 80% of the second most folds, widely spaced eyes, clenched fists with people with common trisomy seen in overlapping fingers, mental retardation, growth this condition live born individuals deficiency and other skeletal and organ anomalies are female Floating-Harbor Short stature, a triangular shaped face with broad Rare Mutations in SRCAP Syndrome (OMIM: bulbous nose, long eyelashes, deep-set eyes and a located in 16p11.2 136140) wide mouth with thin lips chromosomal region [14]. Rubinstein-Taybi syndrome (OMIM: 180849) shows phenotypic overlap with Floating-Harbor syndrome and is caused by mutation in the CREBBP gene, for which SRCAP is a coactivator Fragile X Range of learning disorders, distinctive facial A mutation in the FMR1 Syndrome appearance with large ears and a long face, gene located on the X (OMIM:300624) prominent jaws, speech and language problems chromosome [15,16]. Within this gene, there is a region containing the sequence “CGG”, which is repeated multiple times. Normally the sequence is repeated no more than 55 times in the gene. However, Fragile X Syndrome occurs when a person has more than 200 “CGG” repeats in the FMR1 gene. A person who has more than 55 repeats, but less than 200, is considered a “pre-mutation carrier.” These individuals do not have Fragile X Syndrome themselves but are at risk of having children affected with the disorder since the number of repeats could expand in the next generation Langer-Giedion Short stature, small head, distinctive facial Rare Deletion of 8q23.2 to Syndrome features including deep-set eyes, a bulbous nose, q24.1 chromosomal (OMIM:190350 ) long narrow upper lip and missing teeth region. Candidate gene in this region: EXT1[17] Noonan Syndrome Variable phenotype, which may change with age, 1 in 1,000 to Mutation in the PTPN11 (OMIM:163950) many characteristics of which overlap those of the 2,500 live gene on chromosome Turner syndrome. Short stature and mild mental births 12q24.1[18,19] retardation are the main features of this syndrome. Characteristic facial features including short webbed neck and low-set posteriorly rotated ears Pallister Killian Coarse face with a high forehead, sparse hair on Rare Mosaicism for Syndrome (OMIM: the scalp, an abnormally wide space between the tetrasomy of 601803) eyes, a fold of the skin over the inner corner of the chromosome 12p [20] eyes and a flat nasal bridge with a highly arched palate Patau Syndrome Common features include: heart defects, small 1 in 10,000 Trisomy of chromosome Other name: heads (microcephaly), cleft lip and/or palate, 13 [21] Trisomy 13 small eyes that are close together, extra fingers (polydactyly) and various skeletal abnormalities Pfeiffer Syndrome Craniosynostosis, midface deficiency, cloverleaf 1 in 100,000 Mutations in FGFR1, (OMIM: 101600). skull, broad thumbs, broad great toes FGFR2 and FGFR3 Other name: [22,23] Craniofacial- Skeletal- Dermatologic Dysplasia type 1, 2 and 3. Saethre-Chotzen Acrocephaly, asymmetry of the skull, low set 1 in 25,000 to Mutations in FGFR2 Syndrome hairline, wide and tall forehead, thin, long pointed 50,000 and TWIST1 [24-27] (OMIM:101400). nose, small low-set ears, cleft palate Other name: Acrocephalosyndac tyly type III Smith-Magenis Abnormalities of the craniofacial area such as Rare Mutations in RAI1 gene Syndrome (OMIM: brachycephaly, midface hypoplasia, small ears, [28,29] 182290) broad nose and cleft palate. Overlapping features with Potocki-Lupski syndrome Treacher Collins Various craniofacial abnormalities such as 1 in 25,000 to Mutations in TCOF1 Syndrome antimongoloid slant of the eyes, coloboma of the 50,000 gene [30-33] (OMIM:154500) lid, micrognathia, microtia and other deformity of the ears, hypoplastic zygomatic arches and macrostomia Turner Syndrome People with Turner Syndrome are females and 1 out of 2,500 Females with only one (Monosomy X) typically have short stature, a webbed neck, heart girls X chromosome [34]. defects, swelling of the hands and feet, and Potential involvement of characteristic facial features SHOX gene [35] Velo-Cardio-Facial Highly variable phenotype with cleft palate, heart 1 out of 4000 Point mutations in Syndrome (OMIM: abnormalities, typical faces and over 180 other live births TBX1 [36-38] 192430) clinical findings Waardenburg Characterized by pigmentary abnormalities of the Rare Mutations in PAX3 gene Syndrome (OMIM: hair, skin, eyes and facial structures, including [39]. 193500) broad nasal bridge References 1. 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